The role of viruses in demyelination may be direct, i.e., through infection of glial cells, or indirect e.g., through induction of autoimmunity to a structurally similar normal constituent of myelin (molecular mimicry). The potential of JC virus (JCV) T-antigen to cross-react with myelin basic protein (MBP) was previously pointed out (Annual Report, 1987). However, since JC virus has specificity for glial cells in the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML), the direct mechanism is also a likely possibility. Activities in FY 1988 have focused on the potential of JCV for latency and reactivation in the human brain. Three lines of evidence for JCV latency and reactivation have emerged: (a) the first derives from an animal model of CNS infection in which JCV is inoculated intracerebrally in the neonatal hamster brain. Three days after inoculation on day 1, T- antigen containing cells appeared in the cerebellar external granular layer, hippocampus and periventricular. By 7 days p.i. T-antigen-positive cells case of PML in AIDS reported in the literature (Miller et al., New Eng. J. ed., 1982) has shown that cerebellar granular layer cells are infected in frozen sections of the two folia examined. This infection is restricted to early protein (T-antigen) expression, just as in the neonatal hamster model. Although recent spread into the granular layer form JCV infection of white matter glial cells is also a possibility, early (perinatal) exposure to JCV should be considered in light of the hamster model findings. (c) Our study of the age of distribution of confirmed PML cases showed that, in striking contrast to other CNS infections by DNA viruses, PML has never been described in any child under 5 years of age. Thus, it appears that nay JCV infection of the human CNS early in life is uniquely restricted to abortive infection, as has been observed in the neonatal hamster.